Liver function and survival improve after treatment with Viekirax + Exviera regimen

Hepatitis C patients treated with AbbVie's Viekirax plus Exviera or '3D' regimen saw improvements in liver function biomarkers, had better quality of life and had increased survival compared to untreated people, according to mathematical model studies presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress in Vienna, Austria, in April. One model showed that treatment can be cost-effective at all stages of liver disease.

The advent of direct-acting antiviral agents (DAAs) that can be used in interferon-free regimens has brought about a revolution in chronic hepatitis C treatment. While recently approved DAA regimens produce sustained virological response, or continued undetectable HCV viral load at 12 weeks after completing treatment (SVR12), data are still needed on how viral clearance affects longer-term outcomes such as liver disease progression and survival.

Over years or decades, chronic HCV infection can lead to advanced liver disease including cirrhosis, hepatocellular carcinoma (HCC, a type of liver cancer) and decompensated liver failure. The old interferon-based therapy was generally reserved for people with progressive liver disease due to its poor tolerability.

Many experts believe everyone with hepatitis C can benefit from treatment with the new well-tolerated and highly effective interferon-free therapies, but due to their high cost many payers still want to limit treatment to people with advanced disease.

Short-term liver biomarkers

Heiner Wedemeyer of Medizinische Hochschule in Hannover, Germany, and colleagues looked at short-term markers of liver disease progression among participants in the AbbVie TURQUOISE-II trial, which evaluated the 3D regimen for people with HCV genotype 1 who have compensated cirrhosis (abstract P0808).

The 3D regimen consists of the HCV protease inhibitor paritaprevir with a ritonavir booster plus the NS5A inhibitor ombitasvir in a once-daily coformulation, taken with the NS5B polymerase inhibitor dasabuvir twice daily. In Europe, the coformulation (Viekirax) and dasabuvir (Exviera) are sold separately; in the US the full regimen is sold together under the brand name Viekira Pak.

In this open-label trial, 380 participants were randomly assigned to receive the 3D regimen plus ribavirin for 12 or 24 weeks. More than two-thirds had harder to treat HCV subtype 1a and nearly 60% were treatment-experienced.

The researchers evaluated various non-invasive markers of liver function and fibrosis at 48 weeks after completion of treatment, including non-invasive estimates of liver fibrosis (APRI, FIB-4, Forns Index and FibroTest); hepatic synthetic function, or the liver's ability to produce proteins (albumin level, international normalised ratio [INR], platelet count); and alpha fetoprotein (AFP), a biomarker associated with liver cancer.

SVR12 rates were 92% for people treated for 12 weeks and 97% for those treated for 24 weeks. Overall, successful HCV clearance led to improvements in liver fibrosis, synthetic function and AFP levels. For many of these markers, continued improvement was seen through post-treatment week 48.

All fibrosis indices fell (indicating less fibrosis), starting as soon as treatment week 1, primarily due to decreases in liver enzyme levels used to calculate these scores. Albumin levels rose, platelet counts and INR showed improved blood-clotting ability, and AFP levels fell dramatically.

"Greater improvements in liver function tests were observed in patients with more advanced disease at baseline," the researchers noted.

Liver morbidity and mortality

A series of mathematical models by Scott Johnson from Medicus Economics and colleagues from AbbVie's Global Health Economics and Outcomes Research looked at longer-term outcomes among people treated with the 3D regimen with or without ribavirin.

As described in the first poster (abstract P0850), the researchers developed a Markov health state model to estimate lifetime outcomes – including decompensated cirrhosis, liver cancer, liver transplantation and liver-related death – for people treated in AbbVie phase 3 clinical trials compared to people who received no treatment.

The study population included both previously untreated people and prior non-responders. A majority had absent to moderate fibrosis at baseline (Metavir F0-F2), but nearly 10% had advanced fibrosis (F3), and 12% of treatment-naive and 31% of treatment-experienced study participants had cirrhosis (F4). Overall SVR12 rates were 97% for people with F0-F3 fibrosis, 95% for treatment-naive people with cirrhosis and 97% for treatment-experienced people with cirrhosis.

The model predicted that people treated at all baseline fibrosis stages would have reduced rates of compensated cirrhosis (falling from 78% to 30%), decompensated cirrhosis (from 30% to 5%), HCC (from 17% to 7%), liver transplantation (from 7% to 2%) and liver-related death (from 37% to 9%) compared to people who remained untreated.

In most cases risk reductions ranged from five- to seven-fold lower. However, there was no change in the likelihood of HCC or liver transplantation for people treated when they already had cirrhosis, confirming that people who wait too long continue to have excess risk despite viral clearance.

"The percent of genotype 1 HCV patients developing liver morbidity (compensated cirrhosis, decompensated cirrhosis, HCC, liver transplantation and liver death) was significantly reduced with 3D +/- ribavirin treatment compared to HCV patients who were not treated," the researchers concluded. "Morbidity rates were higher when treatment was deferred to patients with greater baseline disease severity."

Cost and cost-effectiveness

In another model, Johnson's team looked at quality of life and survival among patients in the same clinical trial population treated at different fibrosis stages, compared to the interferon-era strategy of 'watchful waiting' for disease progression (abstract P0806).

Here, they developed a Markov disease utility state-transition model to estimate survival benefits over a lifetime horizon for treated and untreated patients from the perspective of a private US payer, aiming to quantify and estimate a monetary value for life-years (LYs) and quality-adjusted life years (QALYs) gained. They used a threshold of US$100,000 per LY or QALY, a common value in health economics studies.

They found that lifetime survival benefits varied substantially according to the fibrosis stage at treatment initiation. The value of the survival benefit increased sixfold, from US$61,096 for people treated at stage F0 to US$372,130 for those treated at stage F4. The quality-adjusted value of these survival benefits increased nearly threefold, from US$178,313 at stage F0 to US$482,242 at stage F4.

"Treatment with 3D +/- ribavirin prolongs the survival of genotype 1 HCV patients and improves quality of life compared to watchful waiting," they concluded. "The survival costs of watchful waiting (measured as the differential value of survival with treatment relative to no treatment) are substantially greater at more advanced levels of liver fibrosis."

A third mathematical model aimed to determine the average annual lifetime post-treatment medical costs for people treated with the 3D regimen at varying stages of liver disease, again using the same clinical trial population (abstract P0816).

A Markov model of the natural history of HCV was developed based on previous models. Monetary values were based on a systematic literature review of US costs of hepatitis C management. All direct medical expenses were included in the model except for the cost of treatment (drugs, viral load and side-effects monitoring, and management of adverse events).

People who started treatment before they developed fibrosis (stage F0) had an annual average medical cost of US$297, which gradually increased for those treated at stage F1 (US$416), stage F2 (US$563) and stage F3 (US$760). But the cost rose dramatically, to US$3187, for people who were not treated until they developed cirrhosis – more than tenfold greater than the cost of treating at stage F0. Starting treatment at later fibrosis stages resulted in increased average lifetime cost, even as life years decreased.

"Our model suggests that genotype 1 HCV patients who are treated with 3D +/- ribavirin earlier in the disease process incur lower average annual lifetime medical costs compared to patients treated with 3D +/- ribavirin later in the disease process," they concluded. "Consistent with existing literature, annual medical costs were much higher for patients in stage F4 compared to earlier fibrosis stages."

Finally, Johnson's team developed a model to determine the cost-effectiveness of 3D treatment compared to no treatment at different fibrosis stages, using the same patient population (abstract P0815).

Unlike the previous model, this one also included the cost of the drugs and expenses related to adverse events. For drug prices, they used US$922 per day for the 3D regimen and US$14 per day for ribavirin. Estimated adverse event costs ranged from US$318 for skin rash to US$1221 for anaemia to US$2414 for thrombocytopenia (low platelets).

Total costs came out to US$82,783 for treatment plus US$10,445 for other direct medical costs for people treated with the 3D regimen, compared to US$42,636 in direct medical costs for untreated patients.

The model showed that 3D with or without ribavirin was cost-effective compared to no treatment for patients at any fibrosis stage and with any treatment history, with an overall cost of US$16,978 per QALY. Even when looking just at people who had not yet developed fibrosis (F0), treatment was cost-effective at US$37,230 per QALY.

These findings support the growing consensus among medical providers that all people with chronic hepatitis C – regardless of current disease stage – should be eligible for treatment, and that early treatment can be cost-effective.